Coronary heart disease (CHD) or coronary artery disease (CAD) is one of the major causes of death in the United States, accounting for about a third of all mortality. Studies of early CHD sib pairs have identified several risk factors that contribute to CHD (Goldstein, et al., 1973; Hazzard, et al., 1973; and Williams, et al., 1990)*. These dyslipidemic phenotypes and their frequency in cases of early familial coronary disease include: familial hypercholesterolemia (high LDL cholesterol), 3-4%; Type III hyperlipidemia (Apo E2/E2 genotype), 0.5 to 3%; low HDL-cholesterol (HDL-C, also called hypobetalipoproteinemia), 20 to 30%; familial combined hyperlipidemia (FCH--high LDL-cholesterol and/or high triglycerides and/or high VLDL-cholesterol), 20-36%; familial hypertriglyceridemia, about 20%; high Lp(a), 16 to 19%; high homocysteine, 15 to 30%; or no known concordant risk factors 10 to 20% (Williams, et al., 1990). Thus, a familial history of CHD is a risk factor independent of known physiological abnormalities (Hopkins, et al., 1988, Jorde, et al., 1990).
 FNT * A list of References is appended herein, providing full citations of the references.
Several metabolic disorders are associated with increased risk of CHD. These include familial dyslipidemic hypertension (Williams, et al., 1990; Williams, et al., 1993), insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), maturity onset diabetes of the young (MODY), insulin resistant syndrome X (Castro-Cabezas, et al., 1993; Kawamoto, et al., 1996; Landsberg, 1996; Hjermann, 1992; Vague and Raccah, 1992), hyperthyroidism and hypothyroidism (de Bruin, et al., 1993; Blangero, et al., 1996) and obesity (Iverius, et al., 1985). Recent analyses indicate the possibility that a single defect, perhaps the amount of visceral body fat, may underlie many of these syndromes (Hopkins, et al., 1996).
The underlying genetic causes of the majority of CHD deaths are not known. In addition, the genetics of many of the underlying metabolic disorders are not completely understood. These metabolic disorders are generally described as "genetically complex". In addition, the disorders themselves are fairly common in the population, so one possibility is that common alleles at some loci predispose to the disorders, making these alleles difficult to distinguish from common (non-causal) polymorphisms. In addition, the disease causing alleles may have low penetrance. The diseases also develop over a large number of years, thus creating the situation that a relatively minor alteration in the function of the predisposing gene(s) can, over a lifetime, have severe metabolic and phenotypic consequences. Thus, the disease-causing alleles may not be obviously deleterious to gene function. Finally, many metabolic diseases show significant co-morbidity, raising the possibility that multiple phenotypes might be associated with a single gene. The penetrances of the individual disorders may be influenced by different alleles of the gene or by environmental or genetic background effects, and may differ between or within families segregating mutations in the predisposing gene(s).
Some risk factors appear relatively simple genetically. For instance, lipoprotein (a) (Lp(a)) levels are strongly correlated with CHD. Greater than 95% of the variation in Lp(a) protein levels is associated with the gene itself, and is mostly related to the number of Kringle repeats in the gene (DeMeester, et al., 1995). The role of the LDL receptor in lipid metabolism and CHD is another example. The familial hypercholesterolemia (FH) syndrome is a rare syndrome (affecting about 1 in 500 individuals) characterized by very high low-density lipoprotein (LDL)-cholesterol, and very early CHD, usually manifest in the 20s or 30s. Early family studies identified and clinically defined obligate FH heterozygotes, and allowed for the positional cloning of the gene responsible for FH, the LDL receptor. About half of FH index cases can be found to carry mutations in the LDL receptor gene, and at least 373 distinct mutations have been identified in the LDL receptor to date (a database of identified mutations can be found at www.ucl.ac.uk/fh/). These mutations cover the full extent of possible deleterious mutations. Included are point mutations that alter the function of the receptor or the expression of the gene, small insertions and deletions causing frameshifts in the coding region and large genomic rearrangements that cause substantial alterations in the gene's structure, resulting in altered gene expression.
On the other hand, some dyslipidemias appear to be genetically quite complex. For instance, about half of the variation in high-density lipoprotein-C (HDL-C) levels appear to be genetically determined (Friedlander, et al., 1986a; Friedlander, et al., 1986b; Moll, et al., 1989; Perusse, et al., 1989; Prenger, et al., 1992; Cohen, et al., 1994). Defects in several genes are known to cause low HDL-C including apolipoprotein AI (ApoAI) deficiency, apolipoprotein B (ApoB) polymorphisms (Peacock et al., 1992), lipoprotein lipase (LPL) deficiency and lecithin:cholesterol acetyltransferase (LCAT) deficiency (recently reviewed in Funke, 1997). However, in aggregate these known genetic defects account for only a very small proportion of individuals with low HDL. Some studies have shown association of HDL-C levels with the hepatic triglyceride lipase and ApoAI, CIII AIV loci (e.g. Cohen, et al., 1994), indicating that a significant portion of the genetic effects may come from these loci, though other studies have failed to find such an association (Bu, et al., 1994; Maheny, et al., 1995; Marcil, et al., 1996). Additionally, the ApoAI, CIII and AIV loci have been associated with familial combined hyperlipidimia (FCH) in some studies (Wojciechowski, et al., 1991; Tybjaerg-Hansen, et al., 1993, Dallinga-Thie, et al., 1997), but not others (Xu, et al., 1994).
Another complexity of the dyslipidemias is illustrated by the LPL gene. Heterozygotes for some LPL mutations show higher triglycerides and lower HDL-C, and no elevation in LDL-C, and high systolic blood pressure when compared with control individuals (Sprecher, et al., 1996; Deeb, et al., 1996). However there is a significant variation in the extent of these abnormalities when different mutations are compared (Sprecher, et al., 1996). In addition, some LPL mutations are found in individuals with a more classic familial combined hyperlipidemia (FCH), having high LDL-C as well as high TG and low HDL-C (Yang, et al., 1996), and some with insulin-resistant syndrome X (Tenkanen, et al., 1994). Other reports fail to find linkage of FCH with LPL, even in families segregating known LPL mutations (e.g. de Bruin, et al., 1996).
Another illustrative set of examples are the MODY genes (Maturity Onset Diabetes of the Young). In combination, the MODY genes account for about 130 of every 10,000 diabetics. Positional cloning and candidate gene mutation screening have identified causal mutations in four transcription factors regulating pancreatic gene expression (HNF-1.alpha., Yamagata, et al., 1996; HNF-4.alpha., Yamagata, et al., 1996b, HNF 1.beta., Horikawa et al., 1997; and IPF1 Stoffers, et al., 1997) and in glucokinase, a pancreatic beta-cell molecule involved in the sensing of glucose levels. Interestingly, some of the transcription factor mutations are frameshifts, implying a total loss of functional protein from the altered allele. These results indicate that half-normal levels of these transcription factors can have a very specific physiological effect, and disease phenotype, in spite of their synthesis in a large variety of tissues.